Multiple Sclerosis and Pathology Thereof
Multiple sclerosis (MS) is a chronic autoimmune disease common in central nervous system (CNS), the main changes of lesion are early cerebral white matter demyelination and axon loss as, causing various symptoms, including sensory alteration, visual impairment, muscle weakness, melancholy, coordination and speech difficulties, severe fatigue, cognitive disorder, disequilibrium, body heat and pain, etc., which can cause motion disorder and disability in severe case.
MS mostly involves young and middle-aged people, having very high disability rate. Epidemiologic studies suggest that about 2.5 million people suffer from multiple sclerosis around the world; prevalence rate is between 2 and 150 people per 100,000 people according to different countries or particular ethnic groups. Symptoms of 80% MS patients belong to relapsing-remitting (RR), manifested by multiple relapses and remissions, with stable disease during two recurrence periods, as disease symptoms progressively deteriorate, after 10-20 years, about half of RRMS patients will turn into secondary progressive (SP). The remaining 20% MS patients belong to primary progressive (PP), manifested by no remission after the onset of illness, presenting progressive deterioration.
A lot of studies show that various immune cells are involved in pathogenesis of MS, including T cell, B cell and macrophage, etc. Experimental autoimmune encephalomyelitis (EAE) is an organ specific autoimmune disease, occurring in central nervous system, a delayed allergic disease which is induced by active immunity of myelin protein antigens on experimental animals and has chronic, repeated attacking, CNS inflammatory demyelinating characteristics, main pathological features are perivascular inflammatory cell infiltration and myelin sheath response. Mouse EAE (experimental autoimmune encephalomyelitis) model has the same characteristics as human MS in clinical symptom, biochemical index, immunity and pathology and other aspects, thus it is a currently international generally recognized ideal animal model for studying MS (Chinese Journal of Cell Biology, Vol 34, pp. 826-836).
Under normal physiological conditions, under the control of blood-brain barrier (BBB), only a small number of immune cells may enter central nervous system to play a role in immunosurveillance. However, in virus/bacterial infection or inflammatory conditions, a lot of peripheral immune cells may pass blood-brain barrier and enter central nervous system CNS. Inflammatory CD4+ T cells invade CNS, activate microglia cells and recruit inflammatory macrophages to enter CNS, finally leading to destroy of CNS myelin and cell death of oligodendrocytes, which is the pathogenesis of EAE. EAE and multiple sclerosis can be effectively treated and alleviated by inhibiting inflammatory CD4+ T cell migration, preventing it from entering central nervous system. In 2010, the first oral drug FTY720/Gilenya for treating multiple sclerosis was developed by Novartis, the mechanism of which was relieving symptoms of multiple sclerosis by inhibiting inflammatory CD4+ T cell migration.
Existing Drugs and Shortcomings Thereof
The pathogenesis of MS is complex and not entirely clear yet, there is no special effective drug for treating MS. Since significant inflammatory changes exist in acute MS damage, MS treatment has been focusing on anti-inflammation in the past 30 years.
Now there have been 7 drugs approved for treating MS patients, including glatiramer acetate (GA), recombinant interferon β, natalizumab, mitoxantrone, etc. These drugs are respectively suitable for MS with different symptoms, and can reasonably alleviate recurrent multiple sclerosis, reduce disease relapse in part of patients or reduce clinical symptoms. Meanwhile, these drugs have some side effects. For example, a common adverse effect of recombinant interferon β is an influenza-like symptom, continuing for 24-48 h which usually diminishes after 2-3 months. IFN-β1a may cause swelling and pain in injection sites, liver function impairment and severe allergic reaction, etc., IFN-β1b may cause swelling and tenderness in injection sites, occasionally causing local necrosis, slightly increased serum transaminase, leucopenia or anemia. Natalizumab may cause progressive multifocal leukoencephalopathy (PML). Common side effects of mitoxantrone include nausea, baldness, leucopenia, anemia and cardiotoxicity, etc. Therefore, there is the need of great significance to develop new diagnosis and therapeutic approaches directed at the pathogenesis of MS, as well as new effective therapeutic drugs for MS with reduced side effects.
Extracellular Matrix Protein 1
Extracellular matrix protein 1 (ECM1) was found in 1994 as a 85KD glycosylated protein secreted by stromal osteoblast cell line MN7. Researchers have found the human homologous gene of ECM1 in human chromosome 1q21 position in 1997. Later, researches showed that ECM1 played an important regulatory role in cartilagenous osteogenesis, endothelial proliferation and angiogenesis. Since 2002, researchers have found that ECM1 mutations cause lipoid proteinosis and can produce spontaneous ECM1 antibodies in patients suffering from lichen sclerosus, leading to loss of ECM1 function and diseases etc. This indicates the important function of ECM1 gene, which has also been the main direction of ECM1 study in the recent years. However, wild type ECM1 is low in expression level, difficult to purify, and prone to structural changes during purification process, which finally causes activity loss. Uptill now, function of ECM1 in immune system disease has been rarely reported.